GLP-1RAs outperform DPP-4is in preventing hyperkalemia, RASi therapy discontinuation

Individuals with type 2 diabetes (T2D) treated in routine clinical care appear to fare better with glucagon-like peptide-1 receptor agonists (GLP-1RAs) than with dipeptidyl peptidase-4 inhibitors (DPP-4is), with GLP-1Ras being associated with lower rates of hyperkalemia and renin-angiotensin system inhibitor (RASi) medication discontinuation, as shown in an observational study.

In a large cohort of adults with T2D in Stockholm, Sweden, fewer hyperkalemia events occurred among GLP-1RA initiators than among DPP-4i initiators over a median follow-up of 3.9 months. The respective incidence rates were 21.0 and 39.0 per 1,000 person-years. [JAMA Intern Med 2024;doi:10.1001/jamainternmed.2024.3806]

GLP-1RA was associated with 38-percent decrease in the risk of hyperkalemia compared with DPP-4i (weighted hazard ratio [HR], 0.62, 95 percent confidence interval [CI], 0.50–0.76), with 12-month absolute risks of 2.9 percent and 4.6 percent, respectively.

Results for moderate-to-severe hyperkalemia events also favoured GLP-1RAs over DPP-4i (HR, 0.52, 95 percent CI, 0.28–0.84).

“Emerging mechanistic evidence suggests that our findings are plausible,” the investigators said. “By inhibiting or downregulating the Na⁺/H⁺ exchanger isoform 3 in the proximal tubule, GLP1-RAs increase the flow of tubular fluid and the sodium load delivered to the distal nephron, which in turn induces an increase in urinary potassium excretion by the collecting duct,” as demonstrated in a small randomized clinical trial. [Am J Physiol Renal Physiol 2011;301:F355-F363; Front Endocrinol 2021;12:738848; Am J Physiol Renal Physiol 2019;316:F231-F240]

Continued RASi use

In terms of RASi persistence among 21,751 participants who were using the medication at the time of glucose-lowering therapy initiation, GLP-1RA initiators were less likely than DPP-4i initiators to discontinue their RASi medications (146.2 vs 170.2 1,000 person-years). GLP-1RA was associated with persistence to RASi therapy (HR, 0.89, 95 percent CI, 0.82–0.97), with the 12-month absolute risk of RASi discontinuation being 17.2 percent as opposed to 19.1 percent with DPP-4i.

“Although the observational nature of our study does not allow us to determine whether the lower hyperkalemia rates causally explain this finding, many studies show that hyperkalemia often leads to dose reduction or discontinuation of RASi use in clinical practice and that this clinical decision is associated with worse clinical outcomes,” the investigators noted. [Eur J Heart Fail 2018;20:1217-1226; EClinicalMedicine 2022;55:101751]

Taken together, these observational data reinforce the mechanistic basis for the pleiotropic effects of GLP-1RAs on potassium homeostasis, they said. By mitigating hyperkalemia risk, “treatment with GLP-1RAs may enable wider use of the guideline-recommended cardioprotective and renoprotective medications and contribute to improving clinical outcomes in [T2D].”

The analysis included 33,280 individuals with T2D (mean age 63.7 years, 59.7 percent male), among whom 13,633 initiated GLP-1RA and 19,647 started DPP-4i therapy. Compared with DPP-4i users, GLP-1RA users were younger (mean age 60.4 vs 66.0 years), had higher HbA_1c levels (mean, 8.2 percent vs 7.9 percent), higher eGFR (median, 92.9 vs 86.5 mL/min/1.73 m²), and lower urinary albumin-creatinine ratio (median, 10.8 vs 12.9 mg/g). Furthermore, GLP-1RAs users were more likely to have chronic obstructive pulmonary disease (10.5 percent vs 7.3 percent) and psychiatric disorders (15.1 percent vs 9.9 percent).

Intention-to-treat and subgroup analyses (age, sex, cardiovascular comorbidity, and baseline kidney function) yielded consistent findings.